PROJECT 2 Project 2 of the CREATE RDCRC will explore the genetic determinants of ALS and related disorders using a novel and innovative approach in which we capitalize on shared phenotypic elements across this group of disorders. For Project-2 we will enroll and deeply phenotype 500 patients with ALS and related disorders in whom the genetic cause of disease is not currently known. These data will be combined with the deep phenotypic data collected on 200 patients with ALS and related disorders in which the primary genetic cause has already been identified (Project-1). Genetic studies will identify novel genes for ALS and related disorders, and begin to illuminate the factors that modify the natural course of disease and define endophenotypic features/phenotypic elements that cut cross the boundaries of classic disease entities. This will be achieved by examining both common and rare variation in the context of novel gene discovery in familial and sporadic cases and genetic modifiers in the case of established genetic mutations. All genetic analyses will be based on whole exome sequencing and genome-wide array genotyping as a backbone for the genetic architecture of each sample. In addition to the ~700 exomes we will generate from our deeply phenotyped cohort, we have or expect to have access to ~2,500 exomes from patients with ALS and related disorders, which will be used to confirm/validate the findings in our cohort.